Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice

Cao, Hongyan; Fang, Jun; Zhang, Yun-Long; Zou, Lei-Xin; Han, Xiao; Yang, Jie; Yan, Xiao; Li, Pang-Bo; Wang, Hongxia; Guo, Shubin; Li, Huihua

doi:10.1016/j.yjmcc.2019.09.010

Cited by 19 publications

(14 citation statements)

References 26 publications

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“…The immunoproteasome reportedly plays a critical function in regulating inflammation and oxidative stress in different immune and inflammatory diseases (Angeles et al, 2012). Several recent investigations have demonstrated that the immunoproteasome catalytic subunits (such as b2i and b5i) and their corresponding proteasome activities were significantly upregulated in the hearts, and exert a critical role in cardiac hypertrophy induced by Ang II infusion or pressure overload (Li et al, 2018;Cao et al, 2019;Xie et al, 2019). Ang II infusion activates several signaling pathways including AKT/ mTOR, TGF-b/Smad2/3, and NF-kB through Ang II type receptor (AT1R), causing hypertrophy, fibrosis, inflammation, and oxidative stress, finally leading to cardiac hypertrophy and AF (Li et al, 2018;Cao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Casein Kinase II (CK2); Phosphoinositide 3-kinase (PI3K); protein kinase A (PKA); AMP-responsive element binding protein (CREB); myocyte enhancer factor 2 (MEF2). cardiac hypertrophic remodeling in mice (Li et al, 2018;Cao et al, 2019). Therefore, drugs or chemicals inhibiting these immunoproteasome subunits may have anti-hypertrophic and anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, PR-957 attenuates isoproterenol-induced cardiac hypertrophy (Zhang et al, 2015) and prevents LV remodeling and heart failure after myocardial infarction (Day Sharlene et al, 2013). We recently found that PR-957 inhibits DOCA salt-induced cardiac remodeling in mice (Cao et al, 2019). However, its role in regulating Ang II-induced cardiac hypertrophy and the underlying mechanism remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Since PTEN/PI3K/AKT, TGF-b1, and p-IkBa/NF-kB are key signaling pathways that mediate cardiac hypertrophy, fibrosis, and inflammation in the heart and atrial tissues (Li et al, 2018;Cao et al, 2019), we examined the effects of PR-957 on their expression in Ang II-infused hearts. Consistent with our previous findings (Li et al, 2018;Chen et al, 2019), we found that 2-week Ang II infusion significantly decreased PTEN protein level but increased protein levels of p-AKT, p-ERK, TGF-b1, p-p65, and p-IkBa compared with the saline control ( Figures 4A, B).…”

Section: Pr-957 Inhibits Hypertrophic Fibrotic and Inflammatory Sigmentioning

confidence: 99%

“…Our previous recent data revealed that b5i deletion alleviates pressure overload-induced cardiac hypertrophy and fibrosis in a murine model via activating autophagy; conversely, b5i overexpression in transgenic mice aggravates this effect (Xie et al, 2019). Further, genetic ablation and pharmacological inhibition of b5i reduces deoxycorticosterone-acetate (DOCA) salt-induced cardiac remodeling in mice (Cao et al, 2019). Furthermore, b5i deletion decreases the incidence of atrial fibrillation (AF) that associated with inhibition of the inflammatory response, oxidative stress, and fibrosis in the atria of angiotensin II (Ang II)-infused mice (Li et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

Xie

Wang

et al. 2020

Front. Pharmacol.

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Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit b5i promotes cardiac hypertrophy. However, whether b5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a b5i-specific inhibitor, on angiotensin II (Ang II)-induced hypertrophic remodeling in the murine heart. The infusion of Ang II increased immunoproteasome chymotrypsin-like activity and b5i catalytic subunit expression in the heart, whereas PR-957 treatment fully blocked the enhanced immunoproteasome activity caused by Ang II. Moreover, the administration of PR-957 significantly suppressed Ang II-induced cardiac hypertrophy, fibrosis, and inflammation. Mechanistically, PR-957 treatment inhibited phosphatase and tensin homolog on chromosome ten (PTEN) degradation, thereby inhibiting multiple signals including AKT/mTOR, ERK1/2, transforming growth factor-b, and IKB/NF-kB. Furthermore, PTEN blocking by its specific inhibitor VO-OHpic markedly attenuated the inhibitory effect of PR-957 on Ang II-induced cardiac hypertrophy in mice. We conclude that PR-957 blocks PTEN degradation and activates its downstream mediators, thereby attenuating Ang II-induced cardiac hypertrophy. These findings highlight that PR-957 may be a potential therapeutic agent for Ang II-induced hypertrophic remodeling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pr-957 Inhibits Hypertrophic Fibrotic and Inflammatory Sigmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

Xie

Wang

et al. 2020

Front. Pharmacol.

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ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway

et al. 2022

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Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. Graphical abstract TAC-induced downregulation of ATGL results in increased proteasome (β1i/β2i/β5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

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Melatonin inhibits angiotensin II–induced atrial fibrillation through preventing degradation of Ang II Type I Receptor–Associated Protein (ATRAP)

Xie

Shen

et al. 2022

Biochemical Pharmacology

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Genetic ablation and pharmacological inhibition of immunosubunit β5i attenuates cardiac remodeling in deoxycorticosterone-acetate (DOCA)-salt hypertensive mice

Cited by 19 publications

References 26 publications

Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway

Melatonin inhibits angiotensin II–induced atrial fibrillation through preventing degradation of Ang II Type I Receptor–Associated Protein (ATRAP)

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